histrelin and Polycystic-Ovary-Syndrome

In polycystic ovary syndrome (PCOS), the mechanism responsible for abnormal gonadotrophin secretion, elevated serum luteinizing hormone (LH) and normal or low follicle-stimulating hormone (FSH) concentrations has not been elucidated. One proposed mechanism, as suggested by previous studies, is an augmented sensitivity of pituitary LH release and a corresponding insensitivity of pituitary FSH release to gonadotrophin-releasing hormone (GnRH) agonist stimulation. This study was designed to further compare gonadotrophin responses to GnRH agonist stimulation within and between individual patients in a dose-response manner. Each of six PCOS and six normal ovulatory women was administered a single s.c. injection of the GnRH agonist [(imBzl)D-His6, Pro9-NEt]-GnRH (D-His) at a dose of 0.01, 0.1, 1 and 10 micrograms/kg on four separate occasions. Blood samples were obtained over a 72 h period following D-His administration. Gonadotrophin responses were measured by (i) the maximal rise from pretreatment baseline values (delta max); (ii) the maximal percentage change from baseline (%delta max); and (iii) the integrated response (mean of the cumulative sum of deviations from baseline). Within-group and between-group dose-responses were compared by two-factor analysis of variance and further characterized using the 'Flexifit' computer program. Our results showed that in both groups, progressive increases of LH and FSH occurred following D-His at doses of 0.01 and 0.1 microgram/kg. Further increases beyond the 0.1 microgram/kg dose were not observed. In PCOS women, delta max and integrated response for LH were significantly greater than those of normal subjects at each dose tested. %delta max of LH was significantly lower in PCOS, reflecting higher pretreatment baseline LH concentrations in this group.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Adult; Dose-Response Relationship, Drug; Drug Resistance; Female; Follicle Stimulating Hormone; Gonadotropin-Releasing Hormone; Humans; Kinetics; Luteinizing Hormone; Pituitary Gland; Polycystic Ovary Syndrome; Steroids

In polycystic ovary syndrome (PCOS), increased luteinizing hormone (LH) pulse frequency has been attributed to either the hypothalamic gonadotrophin-releasing hormone (GnRH) pulse generator or ovarian oestrogen feedback. To address this issue, a detailed examination of pulsatile LH secretion was undertaken during recovery from GnRH agonist (GnRHa) suppression. Each of six women with PCOS and six normal ovulatory women received daily GnRHa treatment for 14 weeks. Frequent blood samples were collected and assayed for gonadotrophins, androgens and oestrogens before, during and up to 4 weeks after treatment. Women with PCOS had higher basal LH pulse frequency and amplitude and increased serum concentrations of LH, androstenedione, testosterone and oestrone than controls. After 3 months of GnRHa treatment, all these parameters were suppressed with no differences observed between the two groups. One week after cessation of GnRHa, LH pulse frequency promptly returned to pre-treatment range with no between-group differences noted, whereas LH pulse amplitude, serum gonadotrophins and ovarian steroids remained maximally suppressed and equivalent in the two groups. Subsequent LH pulse frequency remained constant while LH pulse amplitude and circulating concentrations gradually increased in parallel with a return of serum oestrogen to pre-treatment values. Despite comparable resumption of LH secretion in the two groups, corresponding androgen concentrations in women with PCOS were greater than those of normal ovulatory women. Thus, the immediate restoration of LH pulse frequency after discontinuing GnRHa treatment is largely independent of ovarian oestrogen production and reflects primacy of the GnRH pulse generator in determining basal LH pulse frequency. Equivalent LH pulse frequency rates in the two groups during the recovery period do not suggest an intrinsic hypothalamic-pituitary hyperactivity in PCOS.

Topics: Adult; Algorithms; Case-Control Studies; Estrogens; Feedback; Female; Follicle Stimulating Hormone; Gonadotropin-Releasing Hormone; Humans; Hypothalamo-Hypophyseal System; Luteinizing Hormone; Ovary; Periodicity; Polycystic Ovary Syndrome

Previously, we reported that short term administration of a highly potent GnRH agonist (GnRHa) for 1 month to patients with polycystic ovarian disease (PCO) resulted in complete suppression of ovarian steroidogenesis without measurable effects on adrenal steroid production. This new study was designed to evaluate the effects of long term GnRHa administration in PCO patients with respect to their hormone secretion patterns and clinical responses. Eight PCO patients and 10 ovulatory women with endometriosis were treated daily with sc injections of [D-His6-(imBzl]),Pro9-NEt]GnRH (GnRHa; 100 micrograms) for 6 months. Their results were compared to hormone values in 8 women who had undergone bilateral oophorectomies. In response to GnRHa, PCO and ovulatory women had rises of serum LH at 1 month, after which it gradually declined to baseline. In both groups FSH secretion was suppressed throughout treatment. Serum estradiol, estrone, progesterone, 17-hydroxyprogesterone, androstenedione, and testosterone levels markedly decreased to values found in oophorectomized women by 1 month and remained low thereafter. In contrast, serum pregnenolone and 17-hydroxypregnenolone were partially suppressed, and dehydroepiandrosterone, dehydroepiandrosterone sulfate, and cortisol levels did not change. Clinically, hyperplastic endometrial histology in three PCO patients reverted to an inactive pattern, and proliferative endometrium in two other PCO patients became inactive in one and did not change in the other. Regression of proliferative endometrial histology occurred in all ovulatory women. Vaginal bleeding occurred in all women studied during the first month of GnRHa administration, after which all but one PCO patient became amenorrheic. Hot flashes were noted by all ovulatory women and by four of eight PCO patients. All PCO patients noted subjective reduction of skin oiliness, and five had decreased hair growth. We conclude that in premenopausal women: 1) chronic GnRHa administration results in apparently complete persistent suppression of ovarian steroid secretion; 2) adrenal steroid secretion is not influenced directly or indirectly; and 3) its use may be helpful in the treatment of endometrial hyperplasia and ovarian androgen excess in women with PCO.

Topics: Androgens; Endometriosis; Estrogens; Female; Follicle Stimulating Hormone; Gonadotropin-Releasing Hormone; Humans; Luteinizing Hormone; Ovary; Polycystic Ovary Syndrome; Progestins; Time Factors